Synthetic analogues of plant hormone abscisic acid (ABA) bearing a yet unexplored head group motif were prepared based on a combination of agrochemical experience, in vivo hits and structure‐based design. It could thus be explored how modifying key parts of ABA's cyclohexenone unit influenced receptor affinity and in vivo efficacy against drought stress in selected crops. Cyano‐cyclopropyl groups proved to be suitable replacements of the cyclohexanone moiety leading to ABA analogues with strong activity in vitro and in vivo. Their efficient and versatile synthesis proceeded via Stille or Sonogashira couplings as the key steps. Combining novel cyano‐cyclopropyl headgroups with previously identified substituents in the terpenoid side chain afforded the most promising effects against drought stress in crops, particularly canola and wheat.

Novel analogues of the plant hormone abscisic acid (ABA) were designed and prepared to explore the impact that modifications of its terpenoid side chain have on receptor affinity and in vivo efficacy against drought stress in selected crops. Their efficient and versatile synthesis proceeded via Stille or Sonogashira couplings, shortening the synthetic route significantly. In line with molecular modelling and X‐ray crystallography studies novel ABA‐derivatives with small alkyl, cycloalkyl or haloalkyl substituents showed strong effects in vitro and in vivo against drought stress in crops, particularly canola and wheat.

The Front Cover shows common iterative steps of modern agrochemical research in the foreground with ears of wheat plants close to being harvested in the background. Inspired by nature, that is, by plant hormone abscisic acid (ABA), novel lead structures targeting drought stress in crops such as wheat or canola have been identified. In vivo SAR studies based on greenhouse trials and chemical optimization were supported by systems biology, in vitro analyses, and X‐ray crystallography. It could thus be explored how modification of the key structural features of ABA influences receptor affinity and in vivo efficacy. As a result, cyano‐cyclopropyl groups proved to be suitable replacements for the cyclohexanone headgroup motif. More information can be found in the full papers by J. Frackenpohl, E. Grill et al. (https://doi.org/10.1002/ejoc.201701687 and https://doi.org/10.1002/ejoc.201701769)

BACKGROUND: Whilst there are several methods to control weeds, which continuously plague farmers around the globe, the application of small molecular compounds is still the most effective technology to date. Plants can evolve to become resistant to PPO-inhibitors, a class of herbicides in commercial use since the 1960s. It is therefore essential to continuously develop new herbicides based on this mode-of-action with enhanced intrinsic activity, an improved resistance profile and favourable physicochemical properties. Based on an Amaranthus PPO crystal structure and subsequent modelling studies, halogen-substituted pyrazoles have been investigated as isosteres of uracil-based PPO-inhibitors. RESULTS: By combining structural features from the commercial PPO-inhibitors tiafenacil and pyraflufen-ethyl and by investigating receptor-binding properties, we identified new promising pyrazole-based lead structures showing strong activity in vitro and in vivo against economically important weeds of the Amaranthus genus: A. retroflexus, and resistant A. palmeri and A. tuberculatus. CONCLUSION:The present work covers a series of novel PPO-inhibiting compounds that contain a pyrazole ring and a substituted thioacetic acid sidechain attached to the core phenyl group. These compounds show good receptor fit in line with excellent herbicidal activity against weeds that plague corn and rice crops with low application rates. This, in combination with promising selectivity in corn, have the potential to mitigate and affect weeds that have become resistant to some of the current market standards. Remarkably, some of the novel PPO-inhibitors outlined herein show efficacies against economically important weeds that were superior to recently commercialized and structurally related tiafenacil.

Nucleosides and nucleotides which are able to undergo covalent hydration in the aglycone ring system are potential inhibitors of the enzymes adenosine deaminase (ADA) and AMP deaminase, respectively. Calculations of the enthalpy of covalent hydration and of enzyme binding energy have been used to design new inhibitors of ADA. The ribosyl triazolotriazine 16, which was synthesized as a result of these calculations, exists predominantly as the covalent hydrate 18 in water and is a potent inhibitor of mammalian ADA (IC(50) 50 nM).